rs201431517

Description

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 209 of the MTFMT protein (p.Ser209Leu). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs201431517, gnomAD 0.07%). This missense change has been observed in individual(s) with combined OXPHOS deficiency and/or Leigh syndrome (PMID: 21907147, 22499348, 24461907, 25058219, 26060307, 27290639). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Arg181Serfs5X. ClinVar contains an entry for this variant (Variation ID: 39827). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Studies have shown that this missense change results in skipping of exon 4 and introduces a premature termination codon (PMID: 21907147, 25911677, 28058511). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

This variant was classified as: Pathogenic. This variant was detected in homozygous state.

This variant has been previously reported as disease-causing and was found twice in our laboratory: once in trans with another pathogenic variant [S125L] in a 12-year-old female with mitochondrial disorder, Leigh disease, intellectual disability, short stature, microcephaly, PDA, brachydactyly, pes planus, congenital hypothyroidism; once homozygous in a 19-year-old male with static encephalopathy, optic atrophy, progressive spastic quadriparesis, elevated lactate, leukoencephalopathy. Variant pathogenic in recessive state; heterozygotes would be carriers.

Published functional studies demonstrate a damaging effect with reduced mitochondrial methionyl-tRNA formyltransferase protein activity (Sinha et al., 2014); This variant is reported to eliminate two exonic splicing enhancers and is predicted to cause skipping of exon 4, resulting in a frameshift and premature stop codon (R181SfsX5) (Tucker et al., 2011); This variant is associated with the following publications: (PMID: 24123792, 22499348, 27111573, 27290639, 24461907, 30911575, 31014978, 25288793, 21907147, 25911677, 26060307, 26968897, 26506407, 28058511, 25058219, 26633545, 23499752, 30569017, 30087118, 30369941, 31589614, 33146414)